Accounts of Chemical Research最新文献

{"title":"Phosphorus Chemistry and the Origin of Life: From N-Phosphoryl Amino Acid to Protocell","authors":"Jianxi Ying,&nbsp;Yan Liu,&nbsp;Songsen Fu,&nbsp;Xiang Gao,&nbsp;Yufen Zhao","doi":"10.1021/acs.accounts.6c00206","DOIUrl":"10.1021/acs.accounts.6c00206","url":null,"abstract":"<p>A central question in origin-of-liferesearch is how biologicalmacromolecules and cellular structures arose from simple precursorsunder prebiotic conditions. This review focuses on the chemical evolutionmodel of <em>N</em>-phosphoryl amino acids (NPAAs) and theirmultifaceted roles in this process. Featuring high-energy P–Nbonds, NPAAs enable intramolecular activation via pentacoordinatephosphorus intermediates, facilitating the formation of homochiralpeptides and nucleotides under mild aqueous conditions. Moreover, <em>N</em>-amino acid-nucleotide conjugates (<em>N</em>-aa-NMPs)drive peptide formation with chiral selection between amino acidsand nucleosides, where the peptide yield for each amino acid is modulatedby specific nucleosides, thereby laying a foundation for a proto-geneticcode. Additionally, amphiphilic NPAA derivatives spontaneously self-assembleinto vesicles and selectively condense peptides at membrane interfaces,whereas the in situ generation of <em>N</em>-fatty acyl aminoacids further enhances membrane stability. Collectively, these findingssupport a phosphorus-centered model for the integrated origin of nucleicacids, proteins, and membranes.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 18","pages":"2854–2866"},"PeriodicalIF":18.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148675461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing Heteroaryl Azoswitches: From Molecular Design to Applications","authors":"Tongtong Dang,&nbsp;Tao Li","doi":"10.1021/acs.accounts.6c00374","DOIUrl":"10.1021/acs.accounts.6c00374","url":null,"abstract":"<p>Azobenzene(Ph-N = N-Ph) and its derivativesare widely studiedin many fields owing to their efficient and reversible <em>E</em>⇄<em>Z</em> photoisomerization. However, the parentazobenzene suffers from performance limitations, including incompletephotoconversion, short thermal half-life, low quantum yield, and relianceon UV light excitation. While specific <em>ortho</em>-substitutionscan substantially improve these properties, further performance enhancementsfor advanced applications remain challenging. In recent years, theemergence of heteroaryl azoswitches (Het-N = N-Het/Ph) has broughtnew development opportunities to this already mature field, benefitingfrom their tunable scaffolds and the distinct features arising fromdiverse heteroaryl motifs. Despite their great potential, heteroarylazoswitches are still at an early stage, and their advancement facesmultiple challenges, including the lack of systematic molecular designprinciples, challenging synthesis, poor solid-state isomerizationefficiency, and insufficient focus on practical implementations.</p><p>In this Account, we introduce our recent efforts toward the developmentof high-performance heteroaryl azoswitches, outlining constructivestrategies from molecular design to functional materials. To beginwith, systematic strategies are presented to overcome key performancetrade-offs in solution: 1) Through synergistic optimization of spatialand electronic structures, (hetero)arylazopyrazoles overcome the inherentlimitations of conventional azobenzenes, enabling (near-)quantitativebidirectional photoconversion and long thermal half-lives up to years.2) By rationally combining heteroaryl scaffolds with substituent effects,visible/solar-light-driven heteroaryl azoswitches are developed toavoid using harmful UV light while offering high bidirectional photoconversionand prolonged thermal half-lives. Remarkably, leveraging the efficientisomerization in solution as an essential prerequisite, (near-)quantitativebidirectional photoconversion is realized in azobispyrazole crystals.Building on this foundation, the first reversible single-crystal-to-single-crystalphotoisomerization of an azo photoswitch is established, challengingthe long-held perception that azo isomerization inevitably compromisessingle crystallinity. Furthermore, the broad application prospectsof heteroaryl azoswitches, ranging from energy storage to photoresponsivesmart materials, are validated. Finally, we discuss the enduring challengesand future opportunities of this emerging field. We anticipate thatthese advancements will inspire subsequent exploration of heteroarylazoswitches and pave the way for their implementation in next-generationfunctional materials.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 18","pages":"2890–2901"},"PeriodicalIF":18.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148821798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electrochemical Postfunctionalization of Polymers: Versatile Strategies for Macromolecular Transformation","authors":"Kohei Taniguchi,&nbsp;Kosuke Sato,&nbsp;Shinsuke Inagi","doi":"10.1021/acs.accounts.6c00464","DOIUrl":"10.1021/acs.accounts.6c00464","url":null,"abstract":"&lt;p&gt;Postsynthetic modification ofpolymers is acrucial strategy fortailoring macromolecular properties and achieving complex architecturesthat are typically inaccessible through the polymerization of availablemonomers alone. However, conventional chemical editing typically relieson stoichiometric amounts of hazardous oxidants or reductants, extremetemperatures, and heavy metal catalysts, presenting significant environmentaland economic challenges. In recent years, the electrochemical transformationapproach has emerged as a powerful, mild, and highly sustainable alternative.Because electrons serve as the sole redox reagent, electrochemicalpostfunctionalization operates under ambient conditions without generatingstoichiometric waste, inherently aligning with the principles of greenchemistry. This approach not only eliminates toxic reagents but alsoprovides simple reaction protocols and enables precise control overthe degree of functionalization by tuning the applied potential orcurrent, thereby enabling systematic tailoring of macromolecular properties.&lt;/p&gt;&lt;p&gt;This review categorizes electrochemical postfunctionalization intofour distinct mechanistic modes. The first mode involves direct activationof polymer films deposited on electrodes, where heterogeneous electrontransfer initiates modifications. The second mode involves directactivation of dissolved polymers, enabling homogeneous transformationsalong the macromolecular chain. The third mode employs redox-mediatedindirect activation, overcoming kinetic barriers and facilitatingpolymer backbone modification. Finally, the fourth mode involves electrochemicallygenerated reactive species that migrate from the electrode to reactwith polymers in solution.&lt;/p&gt;&lt;p&gt;Based on these fundamental modes,we highlight the electrochemicalpostfunctionalization of conjugated polymers. A critical factor governingthese transformations is the solubility of the oxidized (doped) polymerspecies, which determines whether the reaction proceeds in the solidstate or in solution. Careful selection of appropriate reaction conditionsenables highly efficient modifications, allowing precise tuning ofthe optical, structural, and electronic properties of the resultingpolymers. These advances enable the development of next-generationorganic electronic materials.&lt;/p&gt;&lt;p&gt;Furthermore, this review exploresthe application of electrochemicalpostfunctionalization to nonconjugated commodity plastics, includingpolystyrene, poly(vinyl chloride), and poly(vinylidene chloride),to address the global waste crisis. For these chemically inert materials,solution-phase electrochemical activation provides efficient and sustainableupcycling pathways. These strategies enable simultaneous deconstructionof persistent plastic waste and generation of value-added fine chemicals,thereby transitioning waste management toward chemical valorization.&lt;/p&gt;&lt;p&gt;This review demonstrates that electrochemical postfunctionalizationprovides a unified and sustainable platform fo","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 18","pages":"2935–2947"},"PeriodicalIF":18.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148885342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progress and Future Directions for Protein Corona Research","authors":"Christine K. Payne","doi":"10.1021/acs.accounts.6c00455","DOIUrl":"10.1021/acs.accounts.6c00455","url":null,"abstract":"<p>The protein corona refers to the proteins thatadsorb on the surfaceof nanoparticles (NPs) exposed to biological environments. The proteinadsorption process is governed by kinetics and thermodynamics, determinedby the specific features of the NPs, proteins, and the methods usedto form and isolate the corona. NPs are described by an inter-relatedlist of features including core material, surface ligands, diameter,and zeta potential. Proteins are described by many features reflectingsize, structure, and sequence. The methods used to form and isolatethe protein corona include how the NPs and proteins are combined andseparated. The protein corona is often characterized by concentration,the amount of protein adsorbed on the NP, and composition, the inventoryof proteins present in the corona. Determining the composition ofthe protein corona is the first step in understanding the underlyingchemistry, physics, and biology that governs this nano-bio interaction.This review will first discuss the NP, protein, and experimental detailsthat control the formation of the protein corona with a focus on unexpecteddetails. I then discuss the biological complexity that impacts proteincorona experiments. This includes the inherent complexity of biologicalfluids used to form the protein corona, the evolution of the coronaas it moves through a biological system, and the influence of diseasestate on the protein corona. Corona formation depends on a highlymultidimensional experimental space that lends itself to the toolsof machine learning. We highlight our work in this area with modestsuccess predicting the protein corona and point toward limitationsin this area related to data sharing and overall goals in the field.In addition to this fundamental research on the nano-bio interface,two applications in protein corona research are discussed: the useof the protein corona as a diagnostic tool and corona-driven in vivoresponses. In addition, I hope to highlight the value of in-persondiscussions for scientific progress.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 18","pages":"2926–2934"},"PeriodicalIF":18.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148805671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Organometallic Electrochemical Synthesis (OES): Enabling C–H and C–X Bond Functionalization","authors":"Yi-Fan Chen,&nbsp;Yun-Sheng Gong,&nbsp;Rui-Xing Gao,&nbsp;Tian-Sheng Mei","doi":"10.1021/acs.accounts.6c00525","DOIUrl":"10.1021/acs.accounts.6c00525","url":null,"abstract":"&lt;p&gt;Organometallic electrochemicalsynthesis (OES) is a rapidly emergingsynthetic domain that elegantly merges transition metal catalysiswith electrochemistry, offering a powerful and sustainable complementto traditional organic synthesis. At its core, organometallic speciesserve as versatile molecular electrocatalysts, precisely regulatingelectron flow at electrode–solution interfaces and orchestratingcontrollable redox conversions, thereby establishing a unique mechanisticparadigm distinct from conventional organic electrochemistry, whichoften relies on radical pathways. Our group has long focused on OES-enabledC–H (carbon–hydrogen) and C–X (carbon–halogen)bond functionalization under this innovative theoretical framework,aiming to address long-standing challenges in synthetic efficiency,atom economy, and selectivity.&lt;/p&gt;&lt;p&gt;A key advantage of electrochemistryis its ability to achieve precise,real-time modulation of the oxidation states of organometallic intermediatesvia heterogeneous interfacial electron transfer. This strategy circumventsthe major drawbacks of traditional stoichiometric redox reagents,which often interact unfavorably with catalysts and generate largeamounts of toxic byproducts or chemical waste. Anodic oxidation, inparticular, efficiently activates inert C–H bonds under mildconditions, enabling challenging C–H bond cleavage and stereoselectivecarbon–carbon (C–C) and carbon–heteroatom (C–Y)framework formation, while maintaining strict control over the reductiveelimination process. Through rational design and introduction of customchiral ligands, we further manipulate stereoselectivity and achievehighly enantioselective asymmetric functionalization, a critical goalin pharmaceutical and fine chemical synthesis. On the other hand,cathodic reduction primarily facilitates the reductive cross-couplingof carbon–halogen bonds. By eliminating the need for extraneousreducing agents, this approach sustains stable catalytic performanceand avoids issues related to reagent activation, deactivation, andside reactions. Chiral induction strategies, when integrated intothe cathodic catalytic cycle, deliver cross-coupling products withhigh enantiomeric excess. Beyond single-electrode reactions, we furtherexplore paired electrolysis and photoassisted paired electrolysis,which synergize anodic oxidation and cathodic reduction in one cell,significantly boosting electron transfer efficiency and expandingthe scope of synthetically useful transformations.&lt;/p&gt;&lt;p&gt;In this Account,we systematically summarize our recent advancescovering anodic oxidation mediated C–H functionalization, cathodicreductive cross-coupling, and paired electrolysis enabled chemicaltransformations. Rational ligand design, electrode optimization, anddetailed mechanistic studies have afforded a suite of versatile, user-friendlysynthetic protocols. These strategies provide ecofriendly, scalablepathways for the construction of complex molecules and pharmaceuticalintermediates, aligning w","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 18","pages":"2977–2993"},"PeriodicalIF":18.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148885341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Purifying, Profiling, Probing, and Programming: The Chemical Biology of Extracellular Vesicles","authors":"Tian Li,&nbsp;Yu Xiao,&nbsp;Hongyu Chen,&nbsp;Gaoge Sun,&nbsp;Joel W. Roberts,&nbsp;Ying Zhang,&nbsp;Liwei Zhang,&nbsp;Hang Yin","doi":"10.1021/acs.accounts.6c00247","DOIUrl":"10.1021/acs.accounts.6c00247","url":null,"abstract":"<p>Extracellular vesicles (EVs)are membrane-enclosed nanoparticlesthat mediate intercellular communication and have attracted growinginterest as potential diagnostic markers and therapeutic vehicles.At the same time, their nanoscale dimensions, compositional heterogeneity,and context-dependent biogenesis continue to complicate their isolation,characterization, and functional analysis. Many of these challengesare fundamentally rooted in limitations of molecular resolution andspecificity, making EV research amenable to chemical biology approaches.</p><p>In this Account, we summarize work from our laboratory over thepast 15 years in which we have developed chemical biology tools toaddress four recurring methodological needs in EV research: purifyingheterogeneous vesicle subpopulations, profiling their molecular composition,probing their cellular fate, and programming their therapeutic function.</p><p>We began with the challenge of EV isolation. We first discussedmembrane curvature-sensing and lipid-affinity probes as modular reagentsfor the selective enrichment of EV subpopulations based on membranephysical and compositional features. We then turned to molecular profilingof EV contents and presented a structure-resolved lipid MS workflow,including a chiral LC-MS/MS platform, that mapped EV lipidomes atstereoisomeric resolution and revealed PI4P as a low-abundance signalinglipid regulating EV biogenesis under immune stress. To address thelong-standing difficulty of tracking EV fate <em>in vivo</em>, we highlighted the bioorthogonal and genetically encoded labelingstrategies that overcome the nonspecific transfer artifacts of lipophilicdyes, making EV uptake and cargo delivery quantifiable at the molecularlevel. Finally, we described stimulus-responsive engineering approachesfor EV engineering, including photoactivatable prodrug hybrids andpH-responsive nanocarrier designs, which convert EVs into programmabledelivery systems capable of controlled transport across the blood–brainbarrier and enhanced drug action in tumor models.</p><p>Taken together,these studies are not intended to suggest thatchemical biology, on its own, can fully resolve the inherent complexityof EV systems. Rather, they underscore the value of introducing molecularlydefined tools into EV isolation, compositional analysis, traffickingstudies, and functional engineering, thereby rendering longstandingchallenges in the field more experimentally tractable and quantitativelyinterpretable. We hope the design strategies and analytical approachessummarized in this Account will offer a practical reference for researchersworking across EV biology and EV-based translational medicine.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 18","pages":"2867–2880"},"PeriodicalIF":18.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148973134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Binding to Biology: Mechanistic Origins of Cell-Selective Fluorescent Probes","authors":"Haw-Young Kwon,&nbsp;Yubin Kim,&nbsp;Young-Tae Chang","doi":"10.1021/acs.accounts.6c00565","DOIUrl":"10.1021/acs.accounts.6c00565","url":null,"abstract":"<p>Cell-selective fluorescent probeshave becomeindispensable toolsfor visualizing biological complexity, yet their mechanisms of selectivityare still predominantly interpreted through a binding-centric paradigm.This conventional view assumes that selective interaction with a biomoleculartarget─typically a protein or glycan─is sufficient toachieve cellular specificity. However, a growing body of evidencereveals a fundamental inconsistency: probes with high binding affinityoften fail to exhibit cell selectivity, whereas others with poorlydefined or weak binding interactions can display remarkable specificity.These observations suggest that cellular selectivity cannot be explainedsolely by molecular recognition.</p><p>In this Account, we presenta comprehensive mechanistic frameworkthat redefines the origins of cell selectivity of fluorescent probes.Building upon classical protein-oriented live-cell distinction (POLD)and carbohydrate-oriented live-cell distinction (COLD) mechanisms,we expand the conceptual landscape to include gating-oriented live-celldistinction (GOLD), metabolism-oriented live-cell distinction (MOLD),and lipid-oriented live-cell distinction (LOLD) processes. Throughrepresentative examples─including CDr3 and TiY (POLD), BacGOand SLY (COLD), CDg16 and CDr17 (GOLD), CDr20 and NeuO (MOLD), CDgB(LOLD), and CDy1 and CDg18 (multilayered)─we demonstrate thatdiverse physicochemical and biological factors collectively contributeto selective cellular labeling.</p><p>A central theme emerging fromthis work is that cell selectivityis inherently multilayered. Rather than being governed by a singledominant mechanism, selectivity arises from the integration of sequentialprocesses: (i) entry into the cell via transporters or endocytic pathways,(ii) intracellular trafficking, (iii) subcellular localization, and(iv) activation of fluorescence. In many high-performance probes,these processes operate cooperatively, forming a “logic-gated”system in which each step acts as a filter that enhances specificity.</p><p>This multilayered perspective resolves longstanding discrepanciesbetween binding affinity and imaging performance and highlights theimportance of nonbinding mechanisms such as membrane permeability,enzymatic transformation, and lipid environment. Moreover, it suggeststhat cellular selectivity reflects not only molecular identity butalso dynamic cellular states, including metabolism, differentiation,and activation.</p><p>Looking forward, this framework points towarda paradigm shiftin probe design. Instead of optimizing single-target interactions,future strategies will increasingly focus on integrating orthogonalmechanisms to construct probes capable of decoding complex biologicalcontexts. Such approaches will enable more precise visualization ofsubtle cellular phenotypes and may ultimately transform fluorescentprobes into tools for interrogating cellular logic itself.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 18","pages":"2994–3005"},"PeriodicalIF":18.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148821781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-Resolution Imaging of Photocatalytic Activity and Charge Separation by Multimodal Photo-SECM","authors":"Ziyuan Wang,&nbsp;Shu Hu,&nbsp;Michael V. Mirkin","doi":"10.1021/acs.accounts.6c00429","DOIUrl":"https://doi.org/10.1021/acs.accounts.6c00429","url":null,"abstract":"&lt;p&gt;Photocatalytic processes arecentral to many energy and environmentalapplications. Understanding the fundamental parameters that governthese reactions at the nanoscale is essential for the rational designof solar energy conversion systems and sustainable chemical synthesis.In nanostructured photocatalysts, the charge-transfer rate and directionand catalytic activity can vary within nanometer-scale distances acrossdifferent sites─even within a single nanoparticle─dueto structural, compositional, and electronic inhomogeneities. Traditionaltechniques provide bulk-averaged data, thereby obscuring such intrinsicspatial variability and limiting mechanistic insight. Photo-scanningelectrochemical microscopy (photo-SECM) has proven useful for mappinglocal catalytic activity through current-based measurements, but itlacks the capacity to directly probe surface potentials and the drivingforce for light-induced charge-transfer and light-driven catalyticprocesses. The high complexity of underlying mechanisms, which includephotogeneration, separation, and transport of charge carriers, aswell as interfacial charge-transfer processes, necessitates multimodalcorrelative experimental characterizations. However, widely employedcharacterization techniques such as surface photovoltage spectroscopy(SPV) and photoemission electron microscopy (PEEM) operate under vacuumor in air, failing to capture the steady-state driving forces forlight-induced redox reactions.&lt;/p&gt;&lt;p&gt;A recently developed nanoscalephoto-SECM methodology has enabledsimultaneous interrogation of interfacial electron-transfer reactionsand charge separation in particulate and two-dimensional photo(electro)catalysts.In this Account, we discuss the development of a multimodal SECM techniquethat combines surface potentiometry with amperometric reaction ratesmapping to directly resolve the steady-state energetic landscape,along with the spatial activity distribution within individual catalyticdomains. This correlative approach enables simultaneous access toboth kinetics (reaction flux) and thermodynamics (local potential),providing a more complete description of photocatalytic function.The surveyed applications include probing charge separation in a monolayerin-plane heterojunction, high-resolution activity mapping of heterogeneousphotocatalysts by the tunnelling mode of photo-SECM, and amperometric/potentiometricphoto-SECM measurements of photoelectrochemical processes in nanostructuredphotocatalysts &lt;em&gt;in operando&lt;/em&gt;. The ability of multimodalSECM to resolve steady-state interfacial energetics and kinetics undercatalytic turnover was essential for probing a novel planar photocatalystin which flux-responsive charging of cocatalyst surface dynamicallysustains the high local driving force while maintaining efficientseparation, accumulation, and utilization of photogenerated electronsand holes.&lt;/p&gt;&lt;p&gt;Future developments may further extend this platformtoward time-resolvedand dynamic measurements of charge s","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 18","pages":"2902–2913"},"PeriodicalIF":18.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148964675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rational Design of Modular Elastin-like Polypeptide Nanoparticles for Nonviral Gene Delivery","authors":"Feng Qu,&nbsp;David H. Thompson","doi":"10.1021/acs.accounts.6c00176","DOIUrl":"10.1021/acs.accounts.6c00176","url":null,"abstract":"<p>Gene therapy has evolved intoa cornerstone modality in modernmedicine, with applications spanning antisense oligonucleotide treatments,RNA interference therapies, mRNA vaccines, in vivo CAR-T cell therapies,and CRISPR-mediated in vivo gene editing. The demands of this proliferatingtherapeutic approach compel the development of delivery systems thatexcel in achieving target specificity, repeat dosing compatibility,storage stability, and scalable manufacturability. Although viralvectors and lipid nanoparticles (LNPs) have achieved clinical success,they face inherent challenges in fully meeting these evolving requirements,highlighting the need for alternatives. Nonviral gene delivery isa highly complex process that requires the delivery system to strikethe proper balance between plasma and shelf stability, appropriatekinetic response for cargo release in the target biological milieu,and capacity for resorption or clearance from the body to minimizeacute and/or long-term toxicity. Elastin-like polypeptides (ELPs),derived from human tropoelastin motifs, have emerged as promisingscaffolds due to their tunable properties, low immunogenicity, andbiodegradable nature. A growing number of laboratories are embracingthe potential of ELPs to advance novel gene delivery systems towardthese goals. This Account describes our laboratory’s sustainedcontributions in the ELP field over the past decade, culminating inthe layer-by-layer elastin-like polypeptide nucleic acid nanoparticle(LENN) platform, which is a modular and biomanufacturable nonviralgene delivery system. We pioneered a fast organic solvent extraction-precipitationpurification for ELPs that is sequence independent, yields materialwith low endotoxin levels, and preserves the functionality of fusiondomains. LENN assembly is achieved by the electrostatic condensationof nucleic acids using cyclodextrin-polyarginine conjugates to formthe core, followed by coating with ELP shells through reversible host–guestinteractions, producing nanoparticles capable of high RNA encapsulation.This Account presents a head-to-head design comparison of LENN versusLNPs, representative peptide-based vectors, and polymeric nonviralsystems, illustrating the modularity of LENN that allows for independentoptimization of key functional elements. Targeted LENN undergoes rapidinternalization and endosomal escape in EGFR⁺ bladder cancercells, enabling efficient mRNA expression and siRNA knockdown. Mechanisticstudies confirm cellular entry via the clathrin-mediated uptake pathwayand activation of lipid remodeling processes that facilitate cargorelease. In an initial proof-of-concept study, EGF-modified LENN exhibitedtumor association following intravesical administration in orthotopicbladder cancer models. These studies illustrate the modularity ofthe LENN design and its potential as a tunable, biocompatible platformfor nucleic acid therapeutics.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 18","pages":"2843–2853"},"PeriodicalIF":18.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148973133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mosquito Meets Crystal","authors":"Jingxiang Yang,&nbsp;Xiaolong Zhu,&nbsp;Bryan Erriah,&nbsp;Alexander G. Shtukenberg,&nbsp;Michael D. Ward,&nbsp;Bart Kahr","doi":"10.1021/acs.accounts.6c00351","DOIUrl":"10.1021/acs.accounts.6c00351","url":null,"abstract":"&lt;p&gt;Combatting malaria, a disease afflicting more than 250 millionpeople annually according to the World Health Organization (WHO),requires insecticides as part of integrated vector management. Indoorresidual spraying (IRS) of crystalline contact insecticides and insecticide-treatedbed nets (ITNs) decorated with insecticide crystals are estimatedto have reduced malaria mortality in Africa by 60% in the 21st century.However, resistance now threatens malaria control, spurring the developmentof new insecticides, a process that requires substantial resources,anddiscovery time while posingenvironmental risks. Improving the effectivenessof compounds currently in use may be preferable. This &lt;em&gt;Account&lt;/em&gt; provides a brief history of contact insecticides and describes discoveriesfrom our laboratory that suggest paths to faster-acting contact insecticidesbased on the engineering of solid-state forms, either amorphous orcrystalline polymorphs, thereby potentially obviating the need fornew chemicals. Contact insecticides are thought to affect insectsby absorption through the footpads. Prior to our 2017 report on thestructure of a second solid form of DDT, crystal polymorphism wasnot optimized for contact insecticides. Comparative analysis of knockdowntimes for flies and mosquitoes against polymorphs of well-known crystallinecontact insecticides including DDT and its analogs, as well as lindane,deltamethrin, and imidacloprid, established a link between thermodynamiccrystal stability and insect knockdown speed. The relationship betweenthe knockdown by a crystalline contact insecticide and its crystalstructure ultimately arises from crystal thermochemistry. Weak intermolecularinteractions in complex systems and associated shallow potential energyhypersurfaces readily lead to crystalline polymorphs with differentmolecular organizations that vary in crystal free energies and associatedbioavailabilities. Notably, a new form of deltamethrin was 12 timesmore active than the commercial form, and the least stable polymorphof imidacloprid was six and nine times more active against susceptible &lt;em&gt;Anopheles&lt;/em&gt; and &lt;em&gt;Aedes&lt;/em&gt; mosquitoes, respectively,than the commercial, thermodynamically stable form. Some of thesemetastable polymorphs were found to be stable against transformationto their thermodynamically stable forms for months in an idealizedlaboratory setting, approaching WHO guidelines for practical use.The observation of differing polymorph effectiveness demonstratesthat tarsal absorption of molecules from the crystal surfaces by insectsis a key step, and likely a limiting step, in the insecticidal action.Indeed, a persistently amorphous form of deltamethrin dispersed onchalk exhibited dramatically increased efficacy against deltamethrin-resistant &lt;em&gt;Anopheles&lt;/em&gt; mosquitoes from Burkina Faso, revealing that anincreased rate of insecticide uptake overwhelmed all the resistancemechanisms tested. Collectively, this work argues that manipulationof the solid","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 18","pages":"2881–2889"},"PeriodicalIF":18.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148858331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}